This invention relates to compositions and methods for pretreatment of tissue to modify the subsequent cellular response to injury, in particular, treatment of smooth muscle cells and other cells to reduce undesirable proliferation following injury.
Currently, many surgical and percutaneous therapies have been developed to (1) reopen blocked channels, conduits, and other critical lumens, (2) to remove undesirable diseased tissue, and (3) to implant substitute tissue, substitute tissue components, and deliver drugs. While these therapies are effective from a macroscopic perspective, from a cellular perspective, this interventional therapy simultaneously injures cells or cellular components of the manipulated tissues.
Specifically, therapeutic interventions, and especially surgical interventions, can cause unwanted subsequent responses by injured tissue. These can cause complications which can undo the effect of the intervention, or create new problems. For example, PCTA (percutaneous transluminal angioplasty) can recanalize and open stenotic or obstructed atherosclerotic arteries, but the incidental balloon mediated stretch and crush injury to the arterial wall can lead to proliferation of the smooth muscle cells of the media of the artery, resulting in reclosure of the artery ("restenosis") over the following months. This is observed in at least one-third of arteries treated. Another example is in the formation of adhesions after surgery, in which a chain of post-operative events leads to the formation or proliferation of adventitious tissue which binds internal body surfaces together, causing discomfort, organ malfunction and potential morbidity and mortality. This can occur in many tissues and organs, including the large and small intestine, the peritoneum, the heart, the pericardium, lungs, pleura, tendons, spinal discs, and paranasal sinuses.
Various interventions have been proposed to minimize such problems. These include the use of stents and coatings in arteries, for example, as reviewed by Slepian, in "Polymeric Endoluminal Paving" Cardiology Clinics12(14) (November 1994) and Slepian, et al., Circulation88(4):part 2, I-319 (1993), and as described by Hill-West, et al., Proc. Natl. Acad. Sci. USA 91:5967 (1994). In addition, the use of coatings, gels and fabrics may be utilized to prevent abdominal and pelvic adhesions as described by Hill-West, et al., Obst. Gyne. 83:59 (1994). These treatments have varying efficacy, and remain largely experimental.
These treatments are all administered after the injury has occurred, whether balloon angioplasty or surgery or other procedure, allowing the injured cells to initiate the complex cascade processes involved in clotting, complement activation, and cellular response to release of cytokines, inducers of proliferation, and other biologically active molecules. It is very difficult to stop these complex, interrelated processes once they have begun. The treatments described above serve merely to physically intercede between the injured cells and the surrounding tissue and blood, in an effort to minimize the reaction of the cells to these processes.
It is clearly desirable to develop methods and compositions to a priori minimize the reaction of cells and tissues, and of cells nearby or adjacent to them, to a subsequent injury. It is especially desirable to develop methods which are part of the body's normal response to injury and therefore multi-factorial in their response and limited in time, requiring minimal administration of exogenous or foreign material to the patient.
It is therefore an object of the present invention to provide methods and compositions for administration to patients to minimize subsequent cellular response to injury.
It is a further object of the present invention to provide compositions having limited term effect on cells which limits for a defined period of time their ability to overreact to injury.